1. Field of the Invention
This invention relates to the preparation of phosphatase inhibitors that act as phosphotyrosine mimetics. The invention particularly relates to compounds designed to inhibit protein-tyrosine phosphatase 1B, and for the treatment of diabetes.
2. Summary of the Related Art
Protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) play an essential role in the regulation of various cellular functions including cell growth, proliferation, differentiation, metabolism and immune responses. They are therefore potentially important targets for therapeutic intervention in a number of diseases, including cancers and diabetes. PTKs generate phosphotyrosyl (pTyr) residues by mediating the phosphorylation of tyrosyl residues. PTPs, in turn, remove pTyr phophates and may play either positive or negative roles in cellular signal transduction.
At present, about 100 enzymes comprise the PTP family and each is either receptor-like or cytoplasmic. One such enzyme is PTP1B, a prototypic intracellular PTP that is expressed in many human tissues and is implicated as a negative regulator of insulin receptor signaling. Recent studies have shown that a correlation exists between levels of PTP1B and insulin resistance states, suggesting that PTP1B may play a role in the insulin resistance associated with diabetes and obesity. Apparently, PTP1B plays a vital role in the dephosphorylation of the insulin receptor. Further, a knockout study has revealed that mice lacking functional PTP1B exhibit increased sensitivity toward insulin and are resistant to obesity (Elchebly, M. et al., Science 1999, 283, 1544–1548). These studies suggest that PTP1B inhibitors would be useful in the treatment of insulin resistance and obesity. More importantly, such an inhibitor could function as an agent for the treatment of non-insulin dependent diabetes mellitus without inducing hypoglycemia.
To date, many of the previously reported PTP1B inhibitors have been peptide-based, containing negatively charged sulfate or phosphonic acid derivatives. Most of these compounds have been found to be inefficient in crossing cell membranes and are unstable in vivo. More recently, small organic molecules have been identified as potent and selective inhibitors of PTP1B (Larsen, S. et al. WO 00/53583; Larsen, S. et al., WO 99/11606; Sarmieto, M. et al., J. Med. Chem. 2000, 43, 146–155; Wrobel, J. et al., J. Med. Chem. 1999, 42, 3199–3202). Still desired is a PTP1B inhibitor that is even less peptidic in nature such that it increases solubility, absorption, cellular penetration and oral availability.